Evidence suggests a role for the arachidonic acid-derived prostanoid thromboxane (TX) A2 (TXA2) in the cancer setting. For example, aspirin may play a role in the prevention of many common cancers, thought to be largely due to its ability to inhibit the increased generation of arachidonic acid-derived products (e.g., TXA2) arising from the up-regulation of COX-1 and COX-2 in the cancer setting. Numerous clinical trials have been conducted to evaluate the benefits of aspirin or COX inhibitors in the treatment of a range of cancers.
While a number of COX-1/2 metabolites have been implicated in contributing to cancers, including prostaglandin (PG) D2 and PGE2, increased levels of TXA2 and expression of TXA2 synthase and of the TXA2 receptor (the TP) may correlate with a range of cancers. TXA2 has been implicated in several stages of tumor development and progression. This may be due to the ability of the TP to not only activate Gαq/phospholipase C, elevating intracellular calcium concentrations, but also due to its ability to activate the extracellular signal regulated kinase (ERK) cascades and to transactivate the epidermal growth factor receptor (EGFR), promoting cell proliferation and mitogenesis. Furthermore, the TXA2 receptor is also known to robustly couple to Gα12-mediated RhoA activation leading to changes in cell shape, motility and adhesion, processes implicated in cancer cell migration and metastasis.
Additionally, many viruses and other infectious agents, upon infecting a host including humans, cause an increase in prostanoids including thromboxane (TX) A2 (TXA2). This increase in prostanoids, including TXA2, impairs the host's immune response and, thus, can help the infectious agent survive and propagate in the infected host. Such impairment of the host immune response can also facilitate infection by other infectious agents. Thus, initial infection by e.g., the influenza virus can, in turn, result in subsequent infection by and propagation of a second infectious agent (e.g., viral, bacterial, or fungal) thus expanding the underlying infectious disease status and lead to development of secondary diseases such as pneumonia.
Thus there is clinical interest in controlling levels of TXA2.
Attempts to control levels of TXA2 have involved targeting its synthesis. An enzyme called cyclooxygenase (COX) produces prostaglandin (PG) H2 through its enzymatic conversion from the 20 carbon lipid arachidonic acid to generate a series of lipid mediators referred to as the prostanoids. In this synthetic pathway, the COX-derived PGH2 endoperoxide product is converted by a host of specific PG synthases to make the prostaglandins PGD2, PGE2, PGF2α and PGI2 (Prostacyclin) and by TXA synthase to make TXA2. The prostanoids are made in a cell- or tissue-specific manner and mediate a diverse range of physiologic roles in the body. By way of example, TXA2 is predominantly made in platelets and in activated macrophages. Thus, inhibiting COX, such as within platelets or macrophage, should reduce or prevent the synthesis of TXA2. COX inhibitors are associated with the irritation of gastric mucosa, peptic ulceration, and renal failure and may increase the risk of atherothrombosis and myocardial infarction, even with short-term use.
Given these problems with COX inhibitors, there is clinical interest in blocking the function of TXA2 by blocking the TXA2 receptor (the T prostanoid receptor, or in short the TP) at the platelet surface. A compound that binds to the TP antagonistically should inhibit TXA2 binding and platelet aggregation and thus tumor development and progression.
Furthermore, as the primary COX-1/COX-2 product PGH2, an endoperoxide, also binds and activates the TP, antagonists of the TP should also impair its activation by PGH2. Moreover, in addition to its enzymatic conversion into the prostanoids through the COX-1/COX-2 catalyzed reactions, arachidonic acid can also be converted non-enzymatically into the isoprostanes through free-radical mechanisms. Noteworthy, the isoprostane 8-iso-PGF2α is the most abundant isoprostane generated during oxidative injury and actually mediates its actions/signals through the TP. Hence, selective TP antagonists will have the added advantage over COX-1/COX-2 inhibitors, such as aspirin or coxibs, in that they will also inhibit the adverse actions of the isoprostane 8-iso-PGF2α generated during oxidative injury and of the endoperoxide PGH2, in addition to inhibiting the action of TXA2 itself. Unfortunately, existing TP antagonists have proven problematic. For example, they lack efficacy, TP specificity and target other receptors, such as the PGD2, platelet activating factor 4, or Leukotriene D4 receptors.
In humans and primates, but not in other species, TXA2 actually signals through two distinct TP receptor isoforms referred to as TPα and TPβ which are encoded by the same gene and differ exclusively in their distal carboxy-terminal primary amino acid sequences. Furthermore, the current TP antagonists do not discriminate between the two TPα and TPβ receptor isoforms which play similar, but not identical, roles. TPα, for example, is subject to desensitization in ways that TPβ is not and vice versa. Due to their distinct roles, in addition to developing general TP antagonists, there may also be clinical interest in compounds that can selectively interact with one or both isoforms of the TP.